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Novel series of immune agonists

A technology of agonists and compounds, applied in the interdisciplinary field of medicinal chemistry and immunology, which can solve the problems of weak activity, limited clinical practicability, and insufficient immunotherapy effect.

Active Publication Date: 2020-09-25
SHENZHEN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The major side effect of TLR7 agonists is the potential toxicity associated with systemic administration, and overactive TLR7 agonists may trigger fatal and severe cytokine storms, limiting their clinical utility
Weak TLR7 agonists are insufficient to achieve desired immunotherapeutic effects

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0405] Example 1 Detection of TLR7 activation of GY series compounds or drugs (HEK-Blue TM Detection)

[0406] Take HEK-Blue in the logarithmic growth phase TM For hTLR7 cells (purchased from InvivoGen), discard the growth medium (Gibco, C11995500BT, Invivo Gen, ant-nr), take an appropriate amount of 37°C PBS (Hyclone, SH30256.01) and gently wash the cells twice, discard the PBS . Add 2-5mL 37°C PBS, incubate for 1-2min, scrape the cells with a cell scraper and blow gently to disperse them into a single-cell suspension. Count cells and calculate cell concentration using a hemocytometer, using HEK-Blue TM Dectetion solution (purchased from Invivo Gen) to adjust the cell suspension to 2.5 × 10 4 / 180 μL per well for cell plating on 96-well cell culture plates. Stimulate the HEK-Blue TM For hTLR7 cells, three replicate wells were set for each concentration. Incubate for 6-16 hours at 37°C and 5% carbon dioxide. After the incubation, the absorbance value was read at a wave...

Embodiment 2

[0412] Example 2 GY series compound immune cell inflammatory factor activation experiment

[0413] The stimulating effect of GY series compounds or drugs on mouse spleen lymphocytes was detected by ELISA.

[0414] 2-1. Acquisition of mouse spleen lymphocytes

[0415] Take 6-week-old Balb / c mice, kill them by cervical dislocation, take out their spleens under aseptic conditions, use a 1 mL sterile syringe and a 200-mesh cell filter, and put them in 4 mL of mouse lymphocyte separation medium (Daktronics, 7211011 ), quickly grind the spleen to disperse single cells. Transfer the cell homogenate to a 15mL centrifuge tube, slowly add 1mL RPMI 1640 medium (Hyclone, SH30809.01), and use density gradient centrifugation (800×g, 30min) to separate spleen lymphocytes, wash and lyse the erythrocytes, A dispersed spleen lymphocyte suspension was obtained. Count the cells with a hemocytometer and calculate the cell concentration, and adjust the cell suspension to 1×10 with RPMI 1640 comp...

Embodiment 3

[0431] Example 3 CCK8 method to detect the growth inhibitory effect or proliferation effect of GY series compounds or drugs on cells

[0432] Mouse breast cancer 4T1 cells in the logarithmic growth phase (KG338) were washed with PBS, digested with 0.25% trypsin (containing EDTA), digested with DMEM complete medium, centrifuged, and resuspended. Make 4T1 cells a single cell suspension. Count the cells with a hemocytometer and calculate the cell concentration. Use DMEM complete medium to adjust the cell suspension to the target concentration, according to 4×10 3 / 100 μL per well for cell plating on 96-well cell culture plates. After the cells adhered to the wall, the 4T1 cells were stimulated according to the designed GY series compound or drug concentration gradient: 3 replicate wells were set for each concentration. The 96-well cell culture plate that was seeded with 4T1 cells and finished adding drugs was placed in a cell culture incubator, and cultured at 37°C and 5% carbo...

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PUM

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Abstract

The invention provides a series of novel Toll-like receptor 7 micromolecular immune agonists as shown in a formula I in the specification. The invention also provides an application of the immune agonist in activating and amplifying immune cells and lymphocytes and preparing immunomodulatory drugs, immune anti-tumor small molecules and immune anti-tumor macromolecular drugs.

Description

technical field [0001] The invention relates to a series of novel small-molecule immune agonists of Toll-like receptor 7 (TLR7) and uses thereof, belonging to the interdisciplinary field of medicinal chemistry and immunology. [0002] technical background [0003] Toll-like receptor 7 (TLR7) belongs to the natural immune system of animals and plays an important role in the defense and treatment of microbial infections and tumor therapy 1，2 . [0004] TLR7 can be activated by synthetic small chemical molecules as ligands, and at the same time induce immune cells to produce immune cytokines IL-6, TNF-α, IFN-γ, etc. Representative TLR7 small molecule agonists include Imiquimod (https: / / www.drugs.com / cdi / imiquimod-cream-aldara.html, FDA approved clinically for antiviral and cancer treatment), Resiquimod (R848) ( https: / / pubchem.ncbi.nlm.nih.gov / compound / Resiquimod for various innate immune applications). [0005] The major side effect of TLR7 agonists is the potential toxicity...

Claims

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Application Information

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IPC IPC(8): C07D473/18C07D519/00C07F9/6584C07F9/6561C07K7/06C07K5/023A61P35/00A61P37/04A61P31/12A61K31/52A61K31/551A61K31/5377A61K31/675A61K38/07A61K38/08
CPCC07D473/18C07D519/00C07F9/65846C07F9/65616C07K7/06C07K5/0202A61P35/00A61P37/04A61P31/12A61K38/00C07D487/04C07F9/6581C07F9/65583A61K47/55A61K47/64A61K47/62
Inventor 靳广毅王竹林周继程亚娟任素梅谭淑娴秦勉
Owner SHENZHEN UNIV
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